Fused imidazole derivative, preparation method therefor, and medical use thereof
Disclosed are fused imidazole derivatives, preparation methods therefor and medical uses thereof. Specifically, the present disclosure relates to a fused imidazole derivative as shown in general formula (IM), a preparation method therefor, a pharmaceutical composition containing the derivative, and the use of same as a therapeutic agent, in particular the use thereof as a GLP-1 receptor agonist, and the use thereof in the preparation of drugs for the treatment and/or prevention of diabetes.
1. A compound of general formula (IM) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring B is phenyl or 5- or 6-membered heteroaryl;
M is a N atom or a C atom;
is a single bond or double bond; when M is a N atom, is a single bond, and when M is a C atom, is a single bond or double bond;
ring C is 6- to 7-membered heterocyclyl, and the 6- to 7-membered heterocyclyl contains 2 heteroatoms selected from the group consisting of an O atom and an S atom;
ring A is aryl or heteroaryl;
each R 1 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
R 2 is selected from the group consisting of a hydrogen atom, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R 3 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
each R 4 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and cycloalkyl;
each R 5 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
each R 6 is identical or different and is each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, cyano, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, and cycloalkyl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and cycloalkyl;
n is 0, 1, 2 or 3;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2 or 3;
g is 0, 1, 2, 3, 4 or 5; and
q is 0, 1, 2, 3 or 4;
provided that the compound is not:
2. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by general formula (IN) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
Y 5 is an O atom or a S atom;
Y 4 and Y 6 are identical or different and are each independently selected from the group consisting of an O atom, a S atom and —(CR m R n ) k− , provided that Y 4 and Y 6 are not both heteroatoms;
R m and R n are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
k is 1 or 2;
ring B, M, , ring A, R 1 to R 6 , n, m, p and q are as defined in claim 1 .
3. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from the group consisting of phenyl, pyridinyl and thienyl, ring A is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl and
and ring C′ is 5- or 6-membered heteroaryl.
4. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by general formula (IIG) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
G is a C atom or a N atom;
Y 5 is an O atom or a S atom;
Y 4 and Y 6 are identical or different and are each independently selected from the group consisting of an O atom, a S atom and —(CR m R n ) k− , provided that Y 4 and Y 6 are not both heteroatoms;
R m and R n are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
k is 1 or 2;
M, ring A, R 1 to R 6 , n, m, p and q are as defined in claim 1 .
5. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 4 , wherein the compound is represented by general formula (IIGa) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
G is a C atom or a N atom;
Y 5 is an O atom or a S atom;
Y 4 and Y 6 are identical or different and are each independently selected from the group consisting of an O atom, a S atom and —(CR m R n ) k− , provided that Y 4 and Y 6 are not both heteroatoms;
R m and R n are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
k is 1 or 2;
M, ring A, R 1 to R 6 , n, m, p and q are as defined in claim 4 .
6. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 4 , wherein Y 4 and Y 5 are O atoms, and Y 6 is —(CR m R n ) k− ; or, Y 5 and Y 6 are O atoms, and Y 4 is —(CR m R n ) k− ; k is 1 or 2; R m and R n are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, cyano, amino, nitro, hydroxy, and 3- to 8-membered cycloalkyl.
7. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by general formula (IIIN-1) or general formula (IIIN-2) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
k is 1 or 2;
M, ring A, R 1 to R 6 , n, m, p and q are as defined in claim 1 .
8. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein
is selected from the group consisting of
R 3 and m are as defined in claim 1 .
9. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 7 , wherein ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; M is CH.
10. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein
is selected from the group consisting of
R 6 and q are as defined in claim 1 .
11. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein each R 1 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen and C 1-6 alkyl; each R 3 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, oxo and C 1-6 alkyl; each R 4 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen and C 1-6 alkyl; each R 5 is identical or different and each is independently a hydrogen atom or C 1-6 alkyl.
12. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; R 6 are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano and C 1-6 haloalkyl.
13. A compound selected from the group consisting of the following compounds:
or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof.
14. A compound of general formula (IMA) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 alkyl;
ring B is phenyl or 5- or 6-membered heteroaryl;
M is a N atom or a C atom;
is a single bond or double bond; when M is a N atom, is a single bond, and when M is a C atom, is a single bond or double bond;
ring C is 6- to 7-membered heterocyclyl, and the 6 - to 7-membered heterocyclyl contains 2 heteroatoms selected from the group consisting of an O atom and a S atom;
ring A is aryl or heteroaryl;
each R 1 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
R 2 is selected from the group consisting of a hydrogen atom, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R 3 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
each R 4 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and cycloalkyl;
each R 5 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
each R 6 is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, cyano, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, and cycloalkyl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and cycloalkyl;
n is 0, 1, 2 or 3;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2 or 3;
g is 0, 1, 2, 3, 4 or 5; and
q is 0, 1, 2, 3 or 4;
provided that the compound is not:
15. The compound of general formula (IMA) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 14 , being selected from the group consisting of the following compounds:
16. A pharmaceutical composition, comprising the compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , and one or more pharmaceutically acceptable carriers, diluents or excipients.
17. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein each R 6 is identical or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, and cycloalkyl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and cycloalkyl.
18. The compound of general formula (IM) or the tautomer, racemate, enantiomer or diastereomer thereof or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by general formula (IIN) or a tautomer, racemate, enantiomer or diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
Y 5 is an O atom or a S atom;
Y 4 and Y 6 are identical or different and are each independently selected from the group consisting of an O atom, a S atom and —(CR m R n ) k− , provided that Y 4 and Y 6 are not both heteroatoms;
R m and R n are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, and cycloalkyl;
k is 1 or 2;
M, ring A, R 1 to R 6 , n, m, p and q are as defined in claim 1 .